The goal of this research project is investigation of the oncogenic potential of an immunosuppressive drug, cyclophosphamide (CY) in hybrid New Zealand (NZB/NZW) mice. CY is currently used to treat selected patients with systemic lupus erythematosus (SLE). NZB/NZW mice develop autoimmune disease that is analogous to SLE in humans. We have shown that neoplasms develop in 94% of hybrid New Zealand mice treated with CY, 8 mg/kg/day. Tumor incidence in untreated mice was 9%. Ongoing studies are providing verification of the increased incidence of neoplasms in additional groups of CY-treated NZB/NZW mice. Tumor incidence is being monitored in mice receiving corticosteroids. The steroid study should differentiate CY-inducted tumor induction from "native" susceptibility to neoplasia in aged NZB/NZW mice. CY will be given to a second model of connective tissue disease, the arteritis- prone PN mice, and to "non-immune" C57B1/6J mice. In control and treated mice, autoantibody production (anti DNA and anti-RNA) will be monitored. PHA stimulation will be employed to detect suppression of cell-mediated immunity. Two serologic parameters that may predict lymphoma formation will be sought in larger numbers of mice: paraproteins will be detected by immunoelectrophoresis and serum will be tested for antinuclear antibodies by indirect immunofluorescence. The addition of Tilorone to CY therapy has lowered the tumor incidence to 20%; no lymphomas have appeared in NZB/NZW mice receiving both drugs. This encouraging data suggests that selected immune-stimulating agents may protect mice from the oncogenic effects of CY. Additional NZB/NZW mice will be treated with CY plus mestranol and CY plus BCG. Immune responses, RES activity, and interferon will be assayed in these animals as they are observed for tumors. This project should contribute to an improved understanding of factors that predispose to the development of malignancy in autoimmune disease.